Older women develop more cataracts than men of comparable age. It is believed that this is due to the loss of estrogen after menopause. Support for this hypothesis comes from epidemiological studies, which show that hormone replacement therapy reduces the risk of cataract, and from animal studies, which show that estradiol prevents TGF-beta-induced anterior subcapsular cataracts in ovariectomized rats. Our laboratory has been interested in the protective role of estradiol, and has used the TGF-beta cataract model to examine the effects of TGF-beta and estradiol in lenses from normal male and female rats. In the presence of low concentrations of TGF-beta2 (0.15 ng/ml), cultured male rat lenses developed twice as many cataract plaques as female rat lenses. Estradiol (10-8M) prevented cataracts in female lenses, but not male lenses. In parallel, the anterior subcapsular cataract marker, alpha-smooth muscle actin, was up regulated in both male and female rat lenses, but down regulated only in female lenses in the presence of estradiol. These findings suggest that there may be sex-specific differences in the level of estrogen receptors. The TGF-beta2 model has many similarities with human anterior subcapsular cataracts and secondary cataracts. Anterior subcapsular cataracts obscure vision, because of their central location in the optical axis. The cataract is the result of an abnormal accumulation of epithelial cells that produce proteins not normally present in the lens, such as, alpha-smooth muscle actin, types I and III collagen, and fibronectin. In secondary cataracts, posterior capsular opacification occurs after cataract surgery as a result of invasion by residual lens epithelial cells. Wrinkling of the capsule and accumulation of extracellular matrix material are hallmarks of this pathology. Secondary cataracts require YAG laser capsulotomy. Therapeutic alternatives that hold promise in retarding lens cell migration include inhibition by thapsigargin, FGF receptor-1, TGF-beta, and integrin antagonists. Estradiol may fall in this category. However, the current study indicates that male-female differences will need to be considered when testing this alternative.